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Simvastatin

Lake Erie Medical & Surgical Supply DBA Quality Care Products LLC

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use simvastatin safely and effectively. See full prescribing information for simvastatin tablets, USP. Simvastatin Tablets, USP Initial U.S. Approval: 1991 RECENT MAJOR CHANGES(2.1)(2.2)(2.3)(2.4)(2.7)(4)(5.1)(5.2)INDICATIONS AND USAGE Reduce the risk of total mortality by reducing CHD deaths and reduce the risk of non-fatal myocardial infarction, stroke, and the need for revascularization procedures in patients at high risk of coronary events. (1.1) Reduce elevated total-C, LDL-C, Apo B, TG and increase HDL-C in patients with primary hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia. (1.2) Reduce elevated TG in patients with hypertriglyceridemia and reduce TG and VLDL-C in patients with primary dysbeta­lipoproteinemia. (1.2) Reduce total-C and LDL-C in adult patients with homozygous familial hypercholesterolemia. (1.2) Reduce elevated total-C, LDL-C, and Apo B in boys and postmenarchal girls, 10 to 17 years of age with heterozygous familial hypercholesterolemia after failing an adequate trial of diet therapy. (1.2, 1.3)   (1.4)DOSAGE AND ADMINISTRATION Dose range is 5 to 40 mg/day. (2.1) Recommended usual starting dose is 10 or 20 mg once a day in the evening. (2.1) Recommended starting dose for patients at high risk of CHD is 40 mg/day. (2.1) Due to the increased risk of myopathy, including rhabdomyolysis, use of the 80 mg dose of simvastatin tablets should be restricted to patients who have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity. (2.2) Patients who are currently tolerating the 80 mg dose of simvastatin tablets who need to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin should be switched to an alternative statin with less potential for the drug-drug interaction. (2.2) Due to the increased risk of myopathy, including rhabdomyolysis, associated with the 80 mg dose of simvastatin tablets, patients unable to achieve their LDL-C goal utilizing the 40 mg dose of simvastatin tablets should not be titrated to the 80 mg dose, but should be placed on alternative LDL-C-lowering treatment(s) that provides greater LDL-C lowering. (2.2) Adolescents (10 to 17 years of age) with HeFH: starting dose is 10 mg/day; maximum recommended dose is 40 mg/day. (2.5) DOSAGE FORMS AND STRENGTHSTablets: 5 mg; 10 mg; 20 mg; 40 mg; 80 mg (3) CONTRAINDICATIONS Concomitant administration of strong CYP3A4 inhibitors. (4, 5.1) Concomitant administration of gemfibrozil, cyclosporine, or danazol. (4, 5.1) Hypersensitivity to any component of this medication. (4, 6.2) Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels. (4, 5.2) Women who are pregnant or may become pregnant. (4, 8.1) Nursing mothers. (4, 8.3) WARNINGS AND PRECAUTIONS Patients should be advised of the increased risk of myopathy including rhabdomyolysis with the 80 mg dose. (5.1) Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks increase with higher doses and concomitant use of certain medicines. Predisposing factors include advanced age (≥65), female gender, uncontrolled hypothyroidism, and renal impairment. (4, 5.1, 8.5, 8.6) Patients should be advised to report promptly any symptoms of myopathy. Simvastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected. See Drug Interaction table. (5.1) Liver enzyme abnormalities and monitoring: Persistent elevations in hepatic transaminase can occur. Monitor liver enzymes before and during treatment. (5.2) Side Effects(6.1) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.DRUG INTERACTIONS Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3) Interacting Agents Prescribing Recommendations    Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol    Contraindicated with simvastatin    Amiodarone, verapamil, diltiazem    Do not exceed 10 mg simvastatin daily    Amlodipine, ranolazine    Do not exceed 20 mg simvastatin daily    Grapefruit juice    Avoid large quantities of grapefruit juice (>1 quart daily) Coumarin anticoagulants: Concomitant use with simvastatin prolongs INR. Achieve stable INR prior to starting simvastatin. Monitor INR frequently until stable upon initiation or alteration of simvastatin therapy. (7.6) USE IN SPECIFIC POPULATIONS Severe renal impairment: Patients should be started at 5 mg/day and be closely monitored. (2.6, 8.6)


FULL PRESCRIBING INFORMATION: CONTENTS*




FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE


1.1 Reductions in Risk of CHD Mortality and Cardiovascular Events



  • Reduce the risk of total mortality by reducing CHD deaths.
  • Reduce the risk of non-fatal myocardial infarction and stroke.
  • Reduce the need for coronary and non-coronary revascularization procedures.

1.2 Hyperlipidemia



  • Reduce elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and triglycerides (TG), and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hyperlipidemia (Fredrickson type IIa, heterozygous familial and nonfamilial) or mixed dyslipidemia (Fredrickson type IIb).
  • Reduce elevated TG in patients with hypertriglyceridemia (Fredrickson type IV hyperlipidemia).
  • Reduce elevated TG and VLDL-C in patients with primary dysbetalipoproteinemia (Fredrickson type III hyperlipidemia).
  • Reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.

1.3 Adolescent Patients with Heterozygous Familial Hypercholesterolemia (HeFH)





  • There is a positive family history of premature cardiovascular disease (CVD) or
  • Two or more other CVD risk factors are present in the adolescent patient.

1.4 Limitations of Use


2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing


tablets

2.2 Restricted Dosing for 80 mg


first[see Warnings and Precautions (5.1)]

or

dose

2.3 Coadministration with Other Drugs


Patients taking Amiodarone, Verapamil, or Diltiazem

Patients taking Amlodipine or Ranolazine  

2.4 Patients with Homozygous Familial Hypercholesterolemia


is[see Dosage and Administration, Restricted Dosing for 80 mg (2.2)]

2.5 Adolescents (10 to 17 years of age) with Heterozygous Familial Hypercholesterolemia


1 Clinical Studies (14.2)


1Pediatrics.

2.6 Patients with Renal Impairment


[see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)]

2.7 Chinese Patients Taking Lipid-Modifying Doses (≥1 g/day Niacin) of Niacin-Containing Products


Chinese[See Warnings and Precautions (5.1).]

3 DOSAGE FORMS AND STRENGTHS


  • Tablets simvastatin 5 mg are yellow colored, round shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘15’ on the other side.
  • Tablets simvastatin 10 mg are light pink colored, round shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘01’ on the other side.
  • Tablets simvastatin 20 mg are light pink colored, round shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘02’ on the other side.
  • Tablets simvastatin 40 mg are pink colored, round shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘03’ on the other side.
  • Tablets simvastatin 80 mg are pink colored, capsule shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘04’ on the other side.

4 CONTRAINDICATIONS



  • Concomitant administration of strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin and nefazodone) [see Warnings and Precautions (5.1)]. 
  • Concomitant administration of gemfibrozil, cyclosporine, or danazol [see Warnings and Precautions (5.1)].
  • Hypersensitivity to any component of this medication [see Adverse Reactions (6.2)].
  • Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels [see Warnings and Precautions (5.2)].
  • Women who are pregnant or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because HMG-CoA reductase inhibitors (statins) decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, simvastatin tablets may cause fetal harm when administered to a pregnant woman. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. There are no adequate and well-controlled studies of use with simvastatin tablets during pregnancy; however, in rare reports congenital anomalies were observed following intrauterine exposure to statins. In rat and rabbit animal reproduction studies, simvastatin revealed no evidence of teratogenicity. Simvastatin tablets should be administered to women of childbearing age only when such patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug, simvastatin tablets should be discontinued immediately and the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].
  • Nursing mothers. It is not known whether simvastatin is excreted into human milk; however, a small amount of another drug in this class does pass into breast milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require treatment with simvastatin tablets should not breastfeed their infants [see Use in Specific Populations (8.3)].

5 WARNINGS AND PRECAUTIONS

5.1 Myopathy/Rhabdomyolysis


Predisposing

The risk of myopathy, including rhabdomyolysis, is dose related. was

patients

The risk of myopathy, including rhabdomyolysis, is greater in patients on simvastatin 80 mg compared with other statin therapies with similar or greater LDL-C-lowering efficacy and compared with lower doses of simvastatin. Therefore, the 80 mg dose of simvastatin should be used only in patients who have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity [see Dosage and Administration, Restricted Dosing for 80 mg (2.2)]. If, however, a patient who is currently tolerating the 80 mg dose of simvastatin needs to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin, that patient should be switched to an alternative statin with less potential for the drug-drug interaction. Patients should be advised of the increased risk of myopathy, including rhabdomyolysis, and to report promptly any unexplained muscle pain, tenderness or weakness. If symptoms occur, treatment should be discontinued immediately. [See Warnings and Precautions (5.2).]

All patients starting therapy with simvastatin, or whose dose of simvastatin is being increased, should be advised of the risk of myopathy, including rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness or weakness. Simvastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected. cases

surgical

Drug Interactions

posaconazole[See Contraindications (4) and Drug Interactions (7.1).] In vitro [See Drug Interactions (7.1).]

danazol[see Contraindications (4) and Drug Interactions (7.1 and 7.2)].

agents[see Drug Interactions (7.2)]

and[see Drug Interactions (7.7)]

against[see Drug Interactions (7.3) and Table 3 in Clinical Pharmacology (12.3)]

with[see Drug Interactions (7.4)]

[see also Dosage and Administration (2.3), Drug Interactions (7), Clinical Pharmacology (12.3)]
TABLE 1 Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis

Interacting Agents
Prescribing Recommendations

   Itraconazole
   Ketoconazole
   Posaconazole
   Erythromycin
   Clarithromycin
   Telithromycin
   HIV protease inhibitors
   Nefazodone
   Gemfibrozil
   Cyclosporine
   Danazol
   Contraindicated with simvastatin

   Amiodarone
   Verapamil
   Diltiazem
   Do not exceed 10 mg simvastatin daily

   Amlodipine
   Ranolazine
   Do not exceed 20 mg simvastatin daily

   Grapefruit juice
   Avoid large quantities of grapefruit juice (>1 quart daily)

5.2 Liver Dysfunction


Persistent increases (to more than 3X the ULN) in serum transaminases have occurred in approximately 1% of patients who received simvastatin in clinical studies.

[see Clinical Studies (14.1)]



It is recommended that liver function tests be performed before the initiation of treatment, and thereafter when clinically indicated. [see Warnings and Precautions (5.1)]



6 ADVERSE REACTIONS

6.1 Clinical Trials Experience






Scandinavian Simvastatin Survival Study


TABLE 2 Adverse Reactions Reported Regardless of Causality by ≥2% of Patients Treated with Simvastatin and Greater than Placebo in 4S
Simvastatin
(N = 2,221)
%
 Placebo
(N = 2,223)
%
   Body as a Whole 
      Edema/swelling 
      Abdominal pain

2.7
5.9
2.3
5.8
   Cardiovascular System Disorders 
      Atrial fibrillation

5.7
5.1
   Digestive System Disorders 
      Constipation 
      Gastritis

2.2
4.9
1.6
3.9
   Endocrine Disorders 
      Diabetes mellitus

4.2
3.6
   Musculoskeletal Disorders 
      Myalgia

3.7
3.2
   Nervous System/Psychiatric Disorders 
      Headache 
      Insomnia 
      Vertigo

2.5
4
4.5
2.1
3.8
4.2
   Respiratory System Disorders 
      Bronchitis 
      Sinusitis

6.6
2.3
6.3
1.8
   Skin/Skin Appendage Disorders 
      Eczema

4.5
3
   Urogenital System Disorders 
      Infection, urinary tract

3.2
3.1

Heart Protection Study



Other Clinical Studies





Laboratory Tests

[see Warnings and Precautions (5.2)][See Warnings and Precautions (5.1).]

Adolescent Patients (ages 10 to 17 years)

[see Use in Specific Populations (8.4) and Clinical Studies (14.2)]

6.2 Postmarketing Experience




7 DRUG INTERACTIONS

7.1 Strong CYP3A4 Inhibitors, Cyclosporine, or Danazol




[See Warnings and Precautions (5.1) and Clinical Pharmacology (12.3).] [see Contraindications (4)].

in vitro [see Warnings and Precautions (5.1)].

[see Contraindications (4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)]

7.2 Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone


[see Contraindications (4) and Warnings and Precautions (5.1)]

[see Warnings and Precautions (5.1)]

7.3 Amiodarone, Ranolazine, or Calcium Channel Blockers


[see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Table 3 in Clinical Pharmacology (12.3)]

7.4 Niacin


[See Warnings and Precautions (5.1) and Clinical Pharmacology (12.3).]

7.5 Digoxin


[see Clinical Pharmacology (12.3)]

7.6 Coumarin Anticoagulants


7.7 Colchicine


8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy


Pregnancy Category X [See Contraindications (4).]

in utero

2

2




2Reproductive Toxicology

8.3 Nursing Mothers


[see Contraindications (4)]

8.4 Pediatric Use


Doses greater than 40 mg have not been studied in this population. [See Dosage and Administration (2.5), Adverse Reactions (6.1), Clinical Studies (14.2).][see Contraindications (4) and Use in Specific Populations (8.1)].

8.5 Geriatric Use


[See Clinical Pharmacology (12.3).]

[see Clinical Studies (14.1)]

[See Warnings and Precautions (5.1) and Clinical Pharmacology (12.3).]

8.6 Renal Impairment


[See Dosage and Administration (2.6).]

8.7 Hepatic Impairment


[see Contraindications (4) and Warnings and Precautions (5.2)]

10 OVERDOSAGE


22

11 DESCRIPTION


Aspergillus terreus

HSSS25385
Simvastatin


12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action


12.2 Pharmacodynamics


12.3 Pharmacokinetics


in vivo

1414





[see Use in Specific Populations (8.5)]





[see Warnings and Precautions (5.1) and Drug Interactions (7.1)]


TABLE 3 Effect of Coadministered Drugs or Grapefruit Juice on Simvastatin Systemic Exposure
* Results based on a chemical assay except results with propranolol as indicated.
† Results could be representative of the following CYP3A4 inhibitors: ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, and nefazodone.
‡ Simvastatin acid refers to the β-hydroxyacid of simvastatin.
§ The effect of amounts of grapefruit juice between those used in these two studies on simvastatin pharmacokinetics has not been studied.
Double-strength: one can of frozen concentrate diluted with one can of water. Grapefruit juice was administered TID for 2 days, and 200 mL together with single dose simvastatin and 30 and 90 minutes following single dose simvastatin on Day 3.
# Single-strength: one can of frozen concentrate diluted with 3 cans of water. Grapefruit juice was administered with breakfast for 3 days, and simvastatin was administered in the evening on Day 3.
Þ Because Chinese patients have an increased risk for myopathy with simvastatin coadministered with lipid-modifying doses (≥ 1 gram/day niacin) of niacin-containing products, and the risk is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products [see Warnings and Precautions (5.1) and Drug Interactions (7.4)].
Coadministered Drug or Grapefruit Juice
Dosing of Coadministered Drug or Grapefruit Juice
Dosing of Simvastatin
Geometric Mean Ratio
(Ratio* with/without
coadministered drug)
No Effect = 1
AUC
Cmax
   Contraindicated with simvastatin [see Contraindications (4) and Warnings and Precautions (5.1)]
   Telithromycin†
200 mg QD for 4 days
 80 mg
    simvastatin acid‡  
   simvastatin
 12
8.9
 15
5.3
   Nelfinavir†
1250 mg BID for 14 days
 20 mg QD for 28 days
    simvastatin acid‡  
   simvastatin
 6
 6.2
   Itraconazole†
200 mg QD for 4 days
 80 mg
    simvastatin acid‡  
   simvastatin
 13.1
13.1
   Posaconazole
100 mg (oral suspension)
QD for 13 days
200 mg (oral suspension) QD for 13 days
 40 mg
40 mg
    simvastatin acid
   simvastatin
   simvastatin acid
   simvastatin
 7.3
10.3
8.5
10.6
 9.2
9.4
9.5
11.4
   Gemfibrozil
600 mg BID for 3 days
 40 mg
    simvastatin acid  
   simvastatin
 2.85
1.35
 2.18
0.91
   Avoid >1 quart of grapefruit juice with simvastatin [see Warnings and Precautions (5.1)]
   Grapefruit Juice§ (high dose)
200 mL of double-strength TID
60 mg single dose
    simvastatin acid  
   simvastatin
 7
16
   Grapefruit Juice§ (low dose)
8 oz (about 237 mL) of single-strength#
20 mg single dose
    simvastatin acid  
   simvastatin
 1.3
1.9
   Avoid taking with >10 mg simvastatin, based on clinical and/or postmarketing experience [see Warnings and Precautions (5.1)]
   Verapamil SR
240 mg QD Days 1 to 7 then 240 mg BID on Days 8 to 10
 80 mg on
Day 10
    simvastatin acid  
   simvastatin
 2.3
2.5
 2.4
2.1
   Diltiazem
120 mg BID for 10 days
 80 mg on
Day 10
    simvastatin acid  
  simvastatin
 2.69 3.1
 2.69
2.88
   Diltiazem
 120 mg BID for 14 days
 20 mg on Day 14
    simvastatin
 4.6
 3.6
   Amiodarone
    
 400 mg QD for 3 days
 40 mg on
Day 3
    simvastatin acid  
   simvastatin
 1.75 1.76
 1.72
1.79
   Avoid taking with >20 mg simvastatin, based on clinical and/or postmarketing experience [see Warnings and Precautions (5.1)]
   Amlodipine
10 mg QD x 10 days
 80 mg on
Day 10
    simvastatin acid  
   simvastatin
 1.58 1.77
 1.56
1.47
   Ranolazine SR
1000 mg BID for 7 days
 80 mg on
Day 1 and Day 6 to 9
    simvastatin acid  
   simvastatin
 2.26 1.86
 2.28
1.75
   No dosing adjustments required for the following:
   Fenofibrate
160 mg QD x 14 days
 80 mg QD on Days 8 to 14
    simvastatin acid  
   simvastatin
 0.64 0.89
 0.89
0.83
   Niacin extended-releaseÞ
2 g single dose
 20 mg single dose
    simvastatin acid  
   simvastatin
 1.6
1.4
 1.84
1.08
   Propranolol
80 mg single dose
 80 mg single dose
    total inhibitor
 
 
 
   active inhibitor
0.79
0.79
 ↓ from
33.6 to 21.1 ng·eq/mL
↓ from
7 to 4.7 ng·eq/mL



13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility










in vitroin vitroin vivo

2

13.2 Animal Toxicology and/or Pharmacology


CNS Toxicity







14 CLINICAL STUDIES

14.1 Clinical Studies in Adults


Reductions in Risk of CHD Mortality and Cardiovascular Events



3




3 D.R. Taves, Minimization: a new method of assigning patients to treatment and control groups. Clin. Pharmacol. Ther. 15 (1974), pp. 443-453



TABLE 4 Summary of Heart Protection Study Results
† n = number of patients with indicated event
Endpoint
Simvastatin
(N=10,269)
n (%)†
Placebo
(N=10,267)
n (%)†
Risk Reduction
(%)
(95% CI)
p-Value
   Primary 
      Mortality 
      CHD mortality
1,328 (12.9)
587 (5.7)
1,507 (14.7)
707 (6.9)
13 (6-19)
18 (8-26)
p=0.0003
p=0.0005
   Secondary 
      Non-fatal MI 
      Stroke
357 (3.5)
444 (4.3)
574 (5.6)
585 (5.7)
38 (30-46)
25 (15-34)
p<0.0001
p<0.0001
   Tertiary
      Coronary revascularization
      Peripheral and other non-coronary 
      revascularization

513 (5)
450 (4.4)
725 (7.1)
532 (5.2)
30 (22-38)
16 (5-26)
p<0.0001
p=0.006





Simvastatin


Angiographic Studies



Modifications of Lipid Profiles

Primary Hyperlipidemia (Fredrickson type lla and llb)



TABLE 5 Mean Response in Patients with Primary Hyperlipidemia and Combined (mixed) Hyperlipidemia (Mean Percent Change from Baseline After 6 to 24 Weeks)
† median percent change
‡ mean baseline LDL-C 244 mg/dL and median baseline TG 168 mg/dL
§ mean baseline LDL-C 188 mg/dL and median baseline TG 128 mg/dL
|| mean baseline LDL-C 226 mg/dL and median baseline TG 156 mg/dL
21% and 36% median reduction in TG in patients with TG ≤200 mg/dL and TG >200 mg/dL, respectively. Patients with TG >350 mg/dL were excluded
†† mean baseline LDL-C 156 mg/dL and median baseline TG 391 mg/dL.
TREATMENT
 N
TOTAL-C
LDL-C
HDL-C
TG†
   Lower Dose Comparative Study‡
   (Mean % Change at Week 6)
   Simvastatin 5 mg q.p.m.
   Simvastatin 10 mg q.p.m.


109
110

-19
-23

-26
-30

10
12

-12
-15
   Scandinavian Simvastatin Survival Study§
   (Mean % Change at Week 6)
   Placebo
   Simvastatin 20 mg q.p.m.


2223
2221

-1
-28

-1
-38

0
8

-2
-19
   Upper Dose Comparative Study||
   (Mean % Change Averaged at Weeks 18 and 24)
   Simvastatin 40 mg q.p.m.
   Simvastatin 80 mg q.p.m.


433
664

-31
-36

-41
-47

9
8

-18
-24
   Multi-Center Combined Hyperlipidemia Study††
   (Mean % Change at Week 6)
   Placebo
   Simvastatin 40 mg q.p.m
   Simvastatin 80 mg q.p.m


125
123
124

1
-25
-31

2
-29
-36

3
13
16

-4
-28
-33

Hypertriglyceridemia (Fredrickson type IV)


TABLE 6 Six-week, Lipid-lowering Effects of Simvastatin in Type IV Hyperlipidemia Median Percent Change (25th and 75th percentile) from Baseline†
† The median baseline values (mg/dL) for the patients in this study were: total-C = 254, LDL-C = 135, HDL-C = 36, TG = 404, VLDL-C = 83, and non-HDL-C = 215.
TREATMENT
   N    
 Total-C
 LDL-C
 HDL-C
 TG
 VLDL-C
 Non-HDL-C
   Placebo
 74
 +2
(-7, +7)
 +1
(-8, +14)
 +3
(-3, +10)
 -9
(-25, +13)
 -7
(-25, +11)
 +1
(-9, +8)
   Simvastatin 40 mg/day
74
 -25
(-34, -19)
 -28
(-40, -17)
 +11
(+5, +23)
 -29
(-43, -16)
 -37
(-54, -23)
 -32
(-42, -23)
   Simvastatin 80 mg/day
74
 -32
(-38, -24)
 -37
(-46, -26)
 +15
(+5, +23)
 -34
(-45, -18)
 -41
(-57, -28)
 -38
(-49, -32)

Dysbetalipoproteinemia (Fredrickson type III)


TABLE 7 Six-week, Lipid-lowering Effects of Simvastatin in Type III Hyperlipidemia Median Percent Change (min, max) from Baseline†
† The median baseline values (mg/dL) were: total-C = 324, LDL-C = 121, HDL-C = 31, TG = 411, VLDL-C = 170, and non-HDL-C = 291.
TREATMENT
    N    
 Total-C
 LDL-C + IDL
HDL-C
 TG
 VLDL-C + IDL
Non-HDL-C
   Placebo
 7
 -8
(-24, +34)
-8
(-27, +23)
 -2
(-21, +16)
+4
(-22, +90)
-4
(-28, +78)
 -8
(-26, -39)
   Simvastatin 40 mg/day
7
 -50
(-66, -39)
 -50
(-60, -31)
 +7
(-8, +23)
 -41
(-74, -16)
 -58
(-90, -37)
 -57
(-72, -44)
   Simvastatin 80 mg/day
7
 -52
(-55, -41)
 -51
(-57, -28)
 +7
(-5, +29)
 -38
(-58, +2)
 -60
(-72, -39)
 -59
(-61, -46)

Homozygous Familial Hypercholesterolemia



Endocrine Function

14.2 Clinical Studies in Adolescents





TABLE 8 Lipid-lowering Effects of Simvastatin in Adolescent Patients with Heterozygous Familial Hypercholesterolemia (Mean Percent Change from Baseline)
† median percent change
Dosage
 Duration
 N
Total-C
 LDL-C
 HDL-C
 TG†
Apo B
   Placebo
24 Weeks
67
% Change from Baseline
(95% CI)
 1.6
(-2.2, 5.3)
 1.1
(-3.4, 5.5)
 3.6
(-0.7, 8)
 -3.2
(-11.8, 5.4)
-0.5
(-4.7, 3.6)
Mean baseline, mg/dL
(SD)
 278.6
(51.8)
 211.9
(49)
 46.9
(11.9)
 90
(50.7)
 186.3
(38.1)
   Simvastatin
24 Weeks
106
% Change from Baseline
(95% CI)
 -26.5
(-29.6, -23.3)
-36.8
(-40.5, -33)
8.3
(4.6, 11.9)
-7.9
(-15.8, 0)
 -32.4
(-35.9, -29)
Mean baseline, mg/dL
(SD)
 270.2
(44)
 203.8
(41.5)
 47.7
(9)
 78.3
(46)
 179.9
(33.8)



16 HOW SUPPLIED/STORAGE AND HANDLING


Simvastatin Tablets USP, 5 mg








Simvastatin Tablets USP, 10 mg








Simvastatin Tablets USP, 20 mg








Simvastatin Tablets USP, 40 mg








Simvastatin Tablets USP, 80 mg







Store at

17 PATIENT COUNSELING INFORMATION




Patients should be advised about substances they should not take concomitantly with simvastatin [see Contraindications (4) and Warnings and Precautions (5.1)]. Patients should also be advised to inform other healthcare professionals prescribing a new medication or increasing the dose of an existing medication that they are taking simvastatin.

17.1 Muscle Pain


Patients using the 80 mg dose should be informed that the risk of myopathy, including rhabdomyolysis, is increased with use of the 80 mg dose.

17.2 Liver Enzymes


17.3 Pregnancy


17.4 Breastfeeding





Aurobindo Pharma USA, Inc.




Aurobindo Pharma Limited


image of labelSimvastatin

Simvastatin

Simvastatin TABLET, FILM COATED

Product Information

Product Type Human prescription drug label Item Code (Source) NDC:49999-889(NDC:65862-052)
Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety

Ingredient Name Basis of Strength Strength
SIMVASTATIN SIMVASTATIN 20 mg

Inactive Ingredients

Ingredient Name Strength
ASCORBIC ACID
lactose monohydrate
cellulose, microcrystalline
STARCH, CORN
hydroxypropyl cellulose
HYPROMELLOSE 2910 (6 MPA.S)
titanium dioxide
talc
CITRIC ACID MONOHYDRATE
ISOPROPYL ALCOHOL
MAGNESIUM STEARATE
BUTYLATED HYDROXYANISOLE
ferric oxide red
FERRIC OXIDE YELLOW

Product Characteristics

Color Size Imprint Code Shape
pink (Light Pink) 8 mm A;02 ROUND

Packaging

# Item Code Package Description Marketing Start Date Marketing End Date
1 NDC:49999-889-30 30 in 1 BOTTLE
2 NDC:49999-889-90 90 in 1 BOTTLE

Marketing Information

Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA077691 2011-11-22


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